ALZHEIMERS DISEASE AS A SYSTEMIC DISORDER

描述：(改编自申请人的摘要)：这项拨款建议 探索阿尔茨海默病(AD)是一种全身性疾病的假设 由血流量减少引起的慢性三磷酸腺苷缺乏引起的 反应性或糖代谢缺陷。渐进性损害 中枢神经系统非再生性神经元早期表现在中枢神经系统 因为神经元对低血流量的敏感性和 神经元再生和维持线粒体酶的能力。 具体地说，我们将研究全身灌注反应性和 阿尔茨海默病的全身性碳水化合物代谢。这些假设将通过以下方式进行验证 实验方案包括：(1)测量 毒扁豆碱对阿尔茨海默病患者乙酰胆碱能神经元的影响 122I-HIPDM高分辨率正电子发射计算机断层扫描脑血流测定 外周肢体阻力血管内皮依赖性血管扩张的研究 AD患者对止血带(血压袖带)缺血的反应 使用先前开发的多普勒分析方法；(3)评估 18F-脱氧葡萄糖在AD骨骼肌运动中的动力学 正电子发射断层扫描；(4)活体4T磁共振研究 阿尔茨海默病患者体外葡萄糖的氧化磷酸化潜能(5) 利用~(14)C葡萄糖在白细胞中的代谢研究；以及(6)线粒体 阿尔茨海默病患者和正常对照组的白细胞功能测定。 这项建议涉及405名体内284名不同的患者和受试者 体外非侵入性研究。这些程序目前已通过验证 使用劳伦斯伯克利国家实验室独特资源的技术。 这项提议中新的关键实验是在体内进行的方法 骨骼肌体内代谢--外周血管舒张性的研究 FDG-PET与体内骨骼肌氧化的研究 利用4T磁共振波谱研究磷酸化电位。

DESCRIPTION: (Adapted from applicant's abstract): This grant proposes to explore the hypothesis that Alzheimer's disease (AD) is a systemic disease caused by a chronic ATP deficiency resulting from diminished blood flow reactivity or defective glucose metabolism. Progressive damage to the nonregenerative central nervous system neurons is manifested early in the CNS because of the susceptibility of neurons to low blood flow and the limited ability of neurons to regenerate and to maintain mitochondrial enzymes. Specifically, we will investigate the role of systemic perfusion reactivity and systemic carbohydrate metabolism in AD. These hypotheses will be tested by experimental protocols including: (1) measurement of the deficit in acetylcholine neurons in AD by quantification of physostigmine stimulation of cerebral blood flow using high resolution PET with 122I-HIPDM; (2) measurement of endothelium-dependent vasodilatation of peripheral limb resistance vessels in AD patients in response to tourniquet-induced (blood pressure cuff) ischemia using a Doppler analysis method developed in previous; (3) evaluation of kinetics of 18F-fluorodeoxyglucose in exercising skeletal muscle of AD using positron emission tomography; (4) in vivo 4T magnetic resonance studies of oxidative phosphorylation potential in AD patients' (5) in vitro glucose metabolism studies using 14C glucose in leukocytes; and (6) mitochondrial function assays of leukocytes in AD and controls. This proposal involves 284 different patients and subjects in 405 in vivo and in vitro non-invasive studies. The procedures are currently validated technologies using unique resources at Lawrence Berkeley National Laboratory. New critical experiments in this proposal are the method of performing in vivo studies of peripheral vessel relaxivity, the in vivo skeletal muscle metabolism studies using FDG-PET, and the in vivo skeletal muscle oxidative phosphorylation potential studies utilizing 4T magnetic resonance spectroscopy.